Cacaoidin, First Member of the New Lanthidin RiPP Family

Abstract

Lantibiotics are ribosomally synthesized and post‐translationally modified peptides (RiPPs) characterized by the presence of lanthionine or methyllanthionine rings and their antimicrobial activity. Cacaoidin, a novel glycosylated lantibiotic, was isolated from a Streptomyces cacaoi strain and fully characterized by NMR, mass spectrometry, chemical derivatization approaches and genome analysis. The new molecule combines outstanding structural features, such as a high number of d‐amino acids, an uncommon glycosylated tyrosine residue and an unprecedented N,N‐dimethyl lanthionine. This latter feature places cacaoidin within a new RiPP family located between lanthipeptides and linaridins, here termed lanthidins. Cacaoidin displayed potent antibacterial activity against Gram‐positive pathogens including Clostridium difficile. The biosynthetic gene cluster showed low homology with those of other known lanthipeptides or linaridins, suggesting a new RiPP biosynthetic pathway.

Sequence Permutation Generates Peptides with Different Antimicrobial and Antibiofilm Activities

“…In the current APD [ 9 ], 551 AMPs are annotated to be primarily active against Gram-positive bacteria. These include some bacteriocins synthesized and secreted by Gram-positive bacteria to inhibit competitive strains [ 16 , 17 , 18 , 19 ]. In contrast, 316 AMPs in the APD are reported to be active primarily against Gram-negative pathogens [ 9 ].…”

“…The isolation of potent antimicrobials from natural sources is an important approach [ 2 , 3 , 4 , 5 , 6 , 7 ]. Although labor-intensive, this classic approach has the great potential to identify novel candidates, including peptides [ 15 , 16 , 17 , 18 , 19 ]. Recent efforts have extended the search of new antimicrobials to uncultivable bacteria and microbiota [ 18 , 19 ].…”

Combating Antimicrobial Resistance With New-To-Nature Lanthipeptides Created by Genetic Code Expansion

“…Bacterial lanthipeptides exhibit outstanding properties such as conformational rigidity, increased metabolic and chemical stability as well as intense cell permeability that distinguish them from other heat-stable (class-II) and thermo-labile (class-III) bacteriocins ( Alvarez-Sieiro et al, 2016 ). In addition to the four earlier types of lanthipeptides classified based on the biosynthetic mechanisms involved in their structural maturation, the recently discovered modified peptides, including Cocaoidin and Lexapeptide, exhibited novel modification features such as different biosynthetic gene clusters and have been introduced as class V lanthipeptides ( Ortiz-López et al, 2020 ; Xu et al, 2020 ).…”

Formation of an Aminovinyl-Cysteine Residue in Thioviridamide Non-Lanthipeptides Occurs through a Path Independent of Known Lanthionine Synthetase Activity inStreptomyces sp. NRRL S-87

“…The counterparts of TvaFS-87 were known in the biosynthesis of various AviCys-containing RiPPs. Either as a LanD protein (for lanthipeptides [10][11][12]15 ) or as a LanD-like protein (for non-lanthipeptides 6,8,16 ), these flavoproteins share the oxidative decarboxylation activity necessary for AviCys formation and can process the C-terminal Cys residue of a precursor peptide to an enethiol before Michael addition to the upstream Dha/Dhb residue. The homologs of TvaCS-87 and TvaES-87 were previously annotated as hypothetic proteins, with the exception in ref.…”

“…3 Recent survey of the published bacterial genome sequences revealed many tvalike gene clusters, and subsequent product mining in related microorganisms led to a rapid enrichment of the TVA family, in which several new members appear to be promising for cancer treatment. 4,5 In addition to a characteristic thioamide peptide backbone, TVAs contain an unusual thioether residue, 2-aminovinyl-(3-methyl)-cysteine (AviCys), 6 which is shared by a variety of RiPPs including linaridins (e.g., cypemycin 7 and cacaoidin 8 ) and certain lanthipeptide-related RiPPs (e.g., epidermin 9 and microvionin lipolanthines 10 ), as part of a macrocyclic ring system that contains the C-terminal 4 or 6 residues of a precursor peptide (Figure 1A). 4 The process through which an AviCys residue is formed remains poorly understood.…”